This proposal is based on 1) findings in humans that initial insensitivity to ethanol is a predictor of later problems with ethanol in Caucasians 2) our knowledge of the genetic mechanisms underlying sensitivity and insensitivity to ethanol in animals. This proposal will expand to Native Americans and to determine whether or not they have similar reactions to ingested ethanol as do Caucasians. If Native Americans don't have the same or similar risk factors for the development of alcoholism as found in Caucasians then, prevention and treatment of alcoholism for them should be altered. The second portion is to locate genes in selectively bred rodent populations that are responsible for the initial sensitivity or insensitivity to ethanol. Quantitative Trait Loci (QTL) in our selectively bred rat colony (High and Low Alcohol Sensitive as well as in Long and Short sleep mice by others) will be located and candidate genes contained within these QTL will be identified. Finally we will search human data bases, for those QTL or genes, found in rodents, that are responsible for ethanol sensitivity and insensitivity and determine their role in risk factors for alcoholism. During the candidate's career he has been involved in the pharmacogenetic aspects of ethanol's action in animal models and has served as Scientific Director and then Principal Investigator of the University of Colorado Alcohol Research Center. This Center's major focus is the Behavioral Pharmacogenetics of Ethanol Action. Thus the current proposal is a culmination of much of the work of the candidate's work in this Center and in separate grants for rat studies. More recently the candidate has become involved in testing of humans for their reactions to ethanol with an emphasis on Native Americans. The environment is optimal for the studies proposed.